Abstract
Dementia with Lewy bodies (DLB) represents a huge medical need as it accounts for up to 30% of all dementia cases, and there is no cure available. The underyling spectrum of pathology is complex and creates a challenge for targeted molecular therapies. We here tested the hypothesis that leukotrienes are involved in the pathology of DLB and that blocking leukotrienes through Montelukast, a leukotriene receptor antagonist and approved anti-asthmatic drug, might alleviate pathology and restore cognitive functions. Expression of 5-lipoxygenase, the rate-limiting enzyme for leukotriene production, was indeed elevated in brains with DLB. Treatment of cognitively deficient human alpha-synuclein overexpressing transgenic mice with Montelukast restored memory. Montelukast treatment resulted in modulation of beclin-1 expression, a marker for autophagy, and in a reduction in the human alpha-synulcein load in the transgenic mice. Reducing the protein aggregation load in neurodegenerative diseases might be a novel model of action of Montelukast. Moreover, this work presents leukotriene signaling as a potential drug target for DLB and shows that Montelukast might be a promising drug candidate for future DLB therapy development.
Highlights
Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are age-related chronic neurodegenerative syndromes with the common features of cognitive decline, parkinsonian motor symptoms, and with an underlying pathology of alpha-synuclein aggregated in neuronal inclusions, so called Lewy bodies [1, 2]
We demonstrate for the first time that the leukotriene receptor antagonist and anti-asthma medication
The underyling scientific rational is based on the finding that expression of 5-Lox is elevated in DLB brains suggesting that leukotriene levels might be elevated in such brains
Summary
Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are age-related chronic neurodegenerative syndromes with the common features of cognitive decline, parkinsonian motor symptoms, and with an underlying pathology of alpha-synuclein aggregated in neuronal inclusions, so called Lewy bodies [1, 2]. The two syndromes are roofed under the term Lewy body dementias (LBD) [2]. The cognitive deficits and its consequences for the patients rank as one of the key unmet needs of LBD therapy [3]. This is further underscored by the fact that LBD comprises, after Alzheimer’s disease, the second most common type of degenerative dementia in patients older than 65 years. The efficacy of disease-modifying approaches remains to be demonstrated [5, 6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
